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Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
Intramural Research Support Program,
Received 3 March 1998/Returned for modification 28 April
1998/Accepted 23 June 1998
The immune response to pathogens is regulated by a delicate balance
of cytokines. The dysregulation of cytokine gene expression, including
interleukin-12, tumor necrosis factor alpha, and gamma interferon
(IFN-
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of
the Gamma Interferon (IFN-
) Promoter and Subsequent Downregulation
of IFN-
Production
), following human retrovirus infection is well documented. One
process by which such gene expression may be modulated is altered DNA
methylation. In subsets of T-helper cells, the expression of IFN-
, a
cytokine important to the immune response to viral infection, is
regulated in part by DNA methylation such that mRNA expression
inversely correlates with the methylation status of the promoter. Of
the many possible genes whose methylation status could be affected by
viral infection, we examined the IFN-
gene as a candidate. We show
here that acute infection of cells with human immunodeficiency virus
type 1 (HIV-1) results in (i) increased DNA methyltransferase
expression and activity, (ii) an overall increase in methylation of DNA
in infected cells, and (iii) the de novo methylation of a CpG
dinucleotide in the IFN-
gene promoter, resulting in the subsequent
downregulation of expression of this cytokine. The introduction of an
antisense methyltransferase construct into lymphoid cells resulted in
markedly decreased methyltransferase expression, hypomethylation
throughout the IFN-
gene, and increased IFN-
production,
demonstrating a direct link between methyltransferase and IFN-
gene
expression. The ability of increased DNA methyltransferase activity to
downregulate the expression of genes like the IFN-
gene may be one
of the mechanisms for dysfunction of T cells in HIV-1-infected
individuals.
*
Corresponding author. Mailing address: P.O. Box B,
Bldg. 567, Rm. 253, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702-1201. Phone: (301) 846-5610. Fax: (301) 846-7034. E-mail:
Mikovits{at}fcrfv1.ncifcrf.gov.
Molecular and Cellular Biology, September 1998, p. 5166-5177, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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